At the present time, there are no good orally-deliverable drug compositions that target treatment of various colon diseases such as chronic inflammatory diseases of the colon or diseases that require treatment by drugs that are absorbed through the colon. Also, there are no orally-deliverable drug compositions for peptides that release the peptides in a colonic environment where the peptides are not degraded to the same extent as peptides are degraded in the acid environment of the upper GI track, particularly the stomach.
Colon diseases include such conditions such as Crohn's disease, colitis (particularly ulcerative colitis), irritable bowel syndrome and the like. These diseases include a spectrum of inflammatory bowel disorders with overlapping clinical, epidemiologic and pathologic findings but without a definite etiology. Both Crohn's disease (CD) and ulcerative colitis (UC) are characterized by chronic inflammation at various sites of the GI tract, generally the colon (i.e., that part of the intestine from the cecum to the rectum). In treating these disease states, it is difficult to direct drugs that are specifically anti-inflammatory in nature and act topically to the desired site. For example, CD seems to affect the cecum primarily while UC seems to go past the second turn in the colon and affect the splenic flexure.
One of the families of compounds that are used in the treatment of this family of diseases are glucorcorticoids. These are thought to be useful in that the glucocorticoids have the capacity to prevent or suppress the development of the manifestations of this inflammation. The thought is that if the drugs can be administered to the inflamed area, the inflammation will recede and the body will ultimately be able to recover. Unfortunately, there are certain side effects the glucocorticoids exhibit if administered systemically and these side effects can be quite significant in treating any disease state. Another problem stemming from these side effects is that there is no way to deliver the drugs directly to the afflicted portion of the colon. Most of the oral formulations that are presently available disintegrate as they pass through the upper GI tract and thus, the steroids are absorbed into the body systemically and the subject being treated will experience some of the undesirable side effects.
The general approaches to delivering drugs to the colon include: 1) enteric coating designed to release drug in the more alkaline environment of the gastrointestinal tract, 2) bioerodible coatings and matrices, 3) prodrugs, 4) timed-release systems and, 5) sustained release systems that release drug after they transit through the small intestine and reach the large intestine.
It is known that certain hydrocolloids have a chemical structure that is subject to attack by the enzymes that are present in the colon, which enzymes will cause the structure of the hydrocolloids to degrade and breakdown. Thus, it has been thought that if a composition could be prepared that would be made of a drug useful for treating the colonic condition and that would pass through the upper GI tract without releasing the drug but would preferentially release it in the colon, the problem could be solved. Several attempts have been made to use a galactomannan-based composition (such as guar gum) to prepare compositions that are orally-administratable but which do not deliver a drug in the upper GI tract but instead make it through the tract to the colon. None of these have been successful. A paper by Rubinstein and Gilko-Kabir describes a borax-modified guar gum for colonic delivery purposes. However, that procedure requires that guar gum be chemically modified using borax in various concentrations to achieve the desired results. Other attempts have been made using glassy amylose to prepare compositions. These, too, were minimally successful.
It is also known that hydrocolloids that are obtainable from higher plants, such as guar gum, are used to increase the gastric residence time and the mean residence time in the gastrointestinal tract to deliver a drug which has the same bioavailability as the formulation of the drug which gives a systemic release profile. The concept is spelled out in co-pending application U.S. Ser. No. 08/348,515 filed Dec. 1, 1994. A broad range of hydrocolloid gum obtained from higher plants could be used to achieve those ends. The type of drug that could be used in the composition of that invention generally included nonpeptidic drug categories that exhibit a preferential window of absorption in the upper GI tract and/or that are generally susceptible to sustained release.
It has now been discovered that by carefully controlling the amount of a hydrocolloid that is obtainable from higher plants, such as guar gum, a composition can be prepared for compounds that are particularly useful for treating chronic inflammatory diseases of the colon (and other colon disorders such as irritable bowel syndrome, constipation, diarrhea, etc.) and for delivering compounds (e.g. peptides) to the colon for better absorption. The families of compounds for which this is particularly valuable includes the glucocorticoids, anticholenergics, 5-ASA, stimulant laxatives, peptides and certain antibodies.